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Home , Salicylic acid

ACTA FACULTATIS MEDICAE NAISSENSIS

UDC: 547.587.1:615.27 DOI: 10.1515/afmnai-2015-0026

Review article

The Beneficial Biological Properties of

Pavle Randjelović1, Slavimir Veljković1, Nenad Stojiljković1, Dušan Sokolović2, Ivan Ilić3, Darko Laketić4, Dušica Randjelović5, Nebojša Randjelović6

1University of Niš, Faculty of Medicine, Department of Physiology, Niš, Serbia 2 University of Niš, Faculty of Medicine, Department of Biochemistry, Niš, Serbia 3University of Niš, Faculty of Medicine, Institute of Pathology, Niš, Serbia 4Urology Clinic, Clinical Hospital Center „Dr DragišaMišović“ –Dedinje, Belgrade, Serbia 5Pediatric Clinic, Clinical Center Niš, Serbia 6University of Niš, Faculty of Sport and Physical Education, Niš, Serbia

SUMMARY

Salicylic acid is a with beneficial effects on human well-being. Salicylic acid is a phenolic compound and is present in various plants where it has a vital role in protection against pathogenic agents. Natural sources include fruits, vegetables and spices. The most famous and defined effect of salicylic acid is synthesis inhibition. Salicylic acid has anti- inflammatory effects through suppression of transcription of genes for . Most of the pharmacological properties of salicylic acid can be contributed to the inhibition of prostaglandin synthesis. Also, it was discovered that salicylic acid has other in vivo cyclooxygenase-independent pathways. Since salicylic acid does not inhibit cyclooxygenase considerably, the anti-inflammatory effect is not a consequence of direct inhibition of cyclooxygenase activity. Because of its fundamental role, it was suggested that inhibition of nuclear factor kappa B by salicylic acid is one of the key anti-inflammatory mechanisms of action for salicylates. One of the most studied properties of salicylic acid is its antioxidative activity. Salicylic acid is a confirmed inhibitor of oxidative stress. Salicylic acid is capable of binding iron. This fact is significant for antioxidative effect of salicylic acid because iron has an important function in the course of lipid peroxidation.

Key words: salicylic acid, biological activity, , salicylates

Corresponding author: Pavle Randjelović e-mail: [email protected]

Acta facultatis medicae Naissensis 2015;32(4):259-265 259 Review article

INTRODUCTION process of inflammation there is a marked change in the concentration and type of PGs. Salicylic acid (SA) belongs to the group of the First, it was considered that SA inhibits the phytochemicals with beneficial effects on human synthesis of PG through COX inhibition (10). health. Salicylic acid is a phenolic compound and can However, in 1999, a new pathway of PG inhibition be found in plants where it has a crucial role in the was proposed for SA and ASA. Xu et al. (11) showed defense against pathogenic agents (1, 2). It is present in that SA and ASA act anti-inflammatory by suppressing various amounts in fruits, vegetables and spices. It is transcription of genes for COX. Most of the more popular as the main metabolite and active pharmacological effects of SA can be explained by PG component of acetyl salicylic acid (ASA), an anti- synthesis inhibition. Also, it was described that SA has inflammatory drug used in clinical practice for more other COX-independent mechanisms of action (12). than 100 years (3). In the last decade it has been accepted that chronic intake of ASA in low doses can ANTI-INFLAMMATORY EFFECTS be effective in the prevention of cardiovascular disease

(CVD) and colorectal carcinoma (4, 5). This fact It is considered that SA and ASA have equal supports the hypothesis that beneficial health effects of anti-inflammatory properties (13). Since SA does not fruits and vegetables partially depends on the presence inhibit COX considerably, the anti-inflammatory of SA in it. Salicylic acid can be detected in the blood of effect is not mediated through direct inhibition of normal, healthy population without record of ASA COX activity. Moreover, ASA has a short half-life in usage, suggesting the origin from plant-based food (6). the blood. ASA is deacetylated to form SA, which is The effect of bark has been responsible for in vivo effects. It was shown that anti- known since first described it. It was used inflammatory action of SA is mediated by the through history in traditional medicine for treating inhibition of leukocyte function and inhibition of the pain. In the year 1859, an active component, SA, was expression of different proinflammatory genes (14). isolated and synthesized. SA is crystal organic Inducible nitric oxide synthase (iNOS) has an . It is soluble in , while poorly important role in the process of inflammation and soluble in water. Since it has a damaging effect on tissue injury. Similarly to COX-2, the expression of gastric mucosa, in 1897 Felix Hoffman synthesized iNOS is induced by cytokines and lipopolysaccharide buffered form ASA (7). (LPS). This catalyzes the production of nitric oxide (NO) which acts further by activation of INHIBITION OF PROSTAGLANDIN guanylate cyclase as well as by nitration and SYNTHESIS nitrosylation of proteins. Furthermore, NO reacts with superoxide anion and creates peroxynitrite.

Peroxynitrite is highly reactive and is capable of The most investigated and described effect of damaging cells. It was shown that SA inhibits SA is the inhibition of the synthesis of expression of iNOS stimulated by LPS and interferon (PGs)(8). PGs are members of the lipid family and are gamma (IFNγ) in alveolar macrophages of rats (15, produced from polyunsaturated fatty acids by 16). Ruy et al .(17) described the suppression of iNOS enzyme cyclooxygenase (COX). Almost all the cells in by SA in RAW 264.7 cells at post-translational or the human body can make PGs from translational level but not at the level of transcription. which is present in the cell membrane phospholipids. Sakitani et al. (18) also demonstrated the inhibition of After being synthesized, PGs act as autocrine or iNOS expression by SA in hepatocytes at the level of paracrine lipid mediators in maintaining local translation but not transcription. homeostasis in the organism. Prostaglandins have Even though the most studies showed that SA numerous physiological functions like: a) protection inhibits the expression of iNOS in pharmacological of the gastrointestinal tract; b) regulation of the doses, there were some reports with similar results kidney homeostasis; c) regulation of sleep and only with supratherapeutic doses (19). Paradoxically, wakening and d) regulation of body temperature (9). Nishio et al. (20) showed the opposite effect of SA to The synthesis of PGs is generally very small in tissues iNOS expression. They found that without inflammation. On the other hand, during the increases the synthesis of iNOS and NO in vascular smooth muscle cells, although the observed effect was 260 Acta facultatis medicae Naissensis 2015;32(4):259-265 Pavle Randjelović, Slavimir Veljković, Nenad Stojiljković et al.

weak. These contradictory findings suggest that the NF-κB is then transferred to the nucleus where it effect of SA on iNOS expression depends on cell type, binds to κB region in promoter of target genes and experimental conditions and stimulation. regulates transcription. Stimulation of cells by LPS in Sodium salicylate has proved itself as the presence of SA resulted in the lack of LPS-induced successful in suppression of acute inflammatory proteolysis of IκB, which proved that the observed reactions in animals (21). Abramson et al. (13) showed inhibition of NF-κB is mediated by inhibition of that ASA inhibits neutrophil function. It was phosphorylation and/or proteolysis of IκB (24). The suggested that it was a consequence of adenosine serum concentrations of SA between 1 and 2 mM are synthesis induction (22). The results from recent study necessary for anti-inflammatory effects, while have indicated that SA can reduce oxidative-stress concentrations higher than 6 mM are toxic (28). associated renal injury by reducing oxygen free radicals and lipid peroxidation in gentamicin-treated rats (23). ANTIOXIDATIVE PROPERTIES

One of the most studied characteristic of SA is NUCLEAR FACTOR KAPPA B its antioxidative property. Since SA is used as a INHIBITION chemical trap for hydroxyl radical, it was reported that SA could reduce tissue damage caused by hypoxia/reoxygenation (29). However, it is not quite It is known that high concentration of SA can clear if antioxidative property of SA has the influence react with kinases, including mitogen activated on its anti-inflammatory effects. protein kinase (MAPK). Most authors point out that For example, the effect of SA on neutrophils the reaction of SA with kinases is inhibitory. It can be adhesion can be explained by the inhibition of one of the reasons for inhibitory effects of SA on extracellular MAPK activation necessary for integrin several nuclear transcription factors. Among activity (30). Also, it was shown that SA inhibits the transcription factors, the research focus is on the activation of transcription factors like NF-κB (24). One interaction between SA and nuclear factor kappa b of the studies has described a new pharmacological (NF-κB). The mentioned nuclear factor is a key effect of SA as the inhibition of transcription for element in cellular response to inflammatory several cytokines genes (31). Therefore, it is possible stimulus. The inhibition of NF-κB by SA was first that there are additional, undiscovered mechanisms reported by Kopp and Ghosh in 1994 (24) and in of action of SA. many experiments later on (25, 26). Since NF-κB Salicylic acid is a verified inhibitor of oxidative regulates the expression of pro-inflammatory stress. Sagone et al. (32) showed that SA reacted with , cytokines, chemokines, receptors and cell hydroxyl radicals in granulocytes and created adhesion molecules, it is usually named as central metabolites. Also, SA decreased superoxide anion of immune response (27). Because of its radicals by acting on NADPH activity which central role, it was proposed that inhibition of NF-κB decreased reactive oxygen species (ROS) in human by SA is one of the main anti-inflammatory endothelial cells in vitro (33). Salicylic acid can bind mechanisms of action for salicylates (24). iron (Fe2+)(34). This fact is important because Fe2+ has Nuclear factor kappa B is involved in the an important function in the process of lipid control of transcription of many genes not involved in peroxidation. The iron creates not only OH- through immune response. That is why NF-κB is more a Fenton reaction but is involved in the creation of regulator of response to stress than central mediator peroxy and alkoxy radicals (35). of immune response. Nuclear factor kappa B also functions as apoptosis regulator, either as inductor or, more often, as the inhibitor of programmed cell death. CONCLUSION The final effect of NF-κB on apoptosis depends on cell type and inductor type. Nuclear factor kappa B There is no doubt that SA is an important transcription factors are regulated primarily by natural compound widely available in nature with interaction with inhibitory IκB proteins. In most cells, proven and described beneficial biological properties. NF-κB is in cytoplasm in inactive form bound to IκB. According to some authors, salicylic acid deserves an Most NF-κB activators proteolyze IκB. The released

Acta facultatis medicae Naissensis 2015;32(4):259-265 261 Review article epithet of a , ‘‘Vitamin S’’. Most of the phytochemical with numerous health-promoting literature-based data about SA is from studies dealing effects, but further experimental studies using isolated with disease preventive properties of ASA. Even SA are needed to fully understand its biological though SA is the main in vivo metabolite of ASA, we effects. cannot equalize the effect of those two related molecules inside the human body. On the other hand, Acknowledgements natural sources of SA like plants are also loaded with other health-promoting phytochemical which can be This work was supported by the Ministry of Science present in higher quantities. Some of them share and Technological Development, Republic of Serbia described biological effects of SA. In this context, we (grants 43012 and 172061). should not draw straightforward conclusions about SA and human health. Finally, we can conclude that SA is a potent and important naturally occurring

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264 Acta facultatis medicae Naissensis 2015;32(4):259-265 Pavle Randjelović, Slavimir Veljković, Nenad Stojiljković et al.

Povoljna biološka svojstva salicilne kiseline

Pavle Ranđelović1, Slavimir Veljković1, Nenad Stojiljković1, Dušan Sokolović2, Ivan Ilić3, Darko Laketić4, Dušica Ranđelović5, Nebojša Ranđelović6

1Univerzitet u Nišu, Medicinski fakultet, Institut za fiziologiju, Niš, Srbija 2Univerzitet u Nišu, Medicinski fakultet, Institut za biohemiju, Niš, Srbija 3Univerzitet u Nišu, Medicinski fakultet, Institut za patologiju, Niš, Srbija 4Klinika za urologiju, Koliničko-bolnički centar “Dr Dragiša Mišović – Dedinje”, Beograd, Srbija 5Klinika za dečije interne bolesti, Klinički centar Niš, Niš, Niš, Srbija 6Univerzitet u Nišu, Fakultet sporta i fizičkog vaspitanja, Niš, Srbija

SAŽETAK

Salicilna kiselina je fitohemikalija sa povoljnim efektima na ljudsko zdravlje. Salicilna kiselina je fenolna komponenta i prisutna je u različitim biljkama, gde ima važnu ulogu u zaštiti od patogenih agenasa. U prirodi se nalazi u voću, povrću i začinima. Najpoznatiji i najbolje proučen efekat salicilne kiseline je inhibicija sinteze prostanglandina. Salicilna kiselina ostvaruje anti-zapaljensko dejstvo preko supresije gena za ciklooksigenazu. Većina farmakoloških svojstava salicilne kiseline mogu se objasniti inhibicijom sinteze prostanglandina. Otkriveno je da salicilna kiselina pored ovog ima i druga in vivo dejstva. Pošto salicilna kiselina ne inhibira značajno ciklooksigenazu, anti-zapaljensko dejstvo nije posledica direktne inhibicije ovog enzima. Predloženo je da je inhibicija nuklearnog faktora kapa B od strane salicilata jedno od glavnih mehanizama anti-zapaljenskog dejstva salicilata. Jedno od najviše proučavanih svojstava salicilne kiseline je antioksidativna aktivnost. Salicilna kiselina je dokazani inhibitor oksidativnog stresa. Salicilna kiselina ima sposobnost vezivanja gvožđa. Ova činjenica je značajna za antioksidativno dejstvo salicilne kiseline zbog toga što gvožđe ima važnu ulogu u procesu lipidne peroksidacije.

Ključne reči: salicilna kiselina, biološka aktivnost, fitohemikalije, salicilati

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